JP2001335566A - Method for producing n-substituted-5-hydroxy- tetrahydro-2-pyrimidinone - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for efficiently producing an N-substituted-5- hydroxy-tetrahydro-2-pyrimidinone useful as a fiber treating agent, a resin raw material, a resin additive, an agrochemical intermediate and a medicine intermediate, and also to provide a method for efficiently producing an optically active N-substituted asymmetric-5-hydroxy-tetrahydro-2-pyrimidinone useful as a reagent for optical resolution, an agrochemical intermediate, a medicine intermediate and various asymmetric sources such as an asymmetric catalyst, etc. SOLUTION: This method for producing an N-substituted-5-hydroxy- tetrahydro-2-pyrimidinone of formula (3) is characterized by using tris-(2,3- epoxypropyl)-isocyanurate of formula (1) and an amine of formula (2) as raw materials.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to N-substituted-5-hydroxy-tetrahydro-2, which is useful as a fiber treating agent, a resin raw material, a resin additive, an agrochemical intermediate, or a pharmaceutical intermediate.
-Pyrimidinone, and optically active N-substituted asymmetric-5-hydroxy-tetrahydro-useful as various existing chiral sources such as optical resolving agents and their raw materials for various optically active uses, agricultural chemicals, pharmaceutical intermediates and other asymmetric catalysts. It relates to a method for producing 2-pyrimidinone.

[0002]

BACKGROUND OF THE INVENTION 5-Hydroxy-tetrahydro-2-pyrimidinone derivatives are commonly used as fiber treatment agents,
Resin raw materials, resin additives, agricultural chemical intermediates, pharmaceutical intermediates, etc.
Further, it is known to be useful as various existing chiral sources such as optical resolving agents and their raw materials, agricultural chemical intermediates, pharmaceutical intermediates, and other asymmetric catalysts for various optically active uses. In particular, regarding the pharmaceutical intermediate, Journal of Medicinal Chemistry (J. Med. Chem.), 42.
Vol. 135, p. 135 (1999) and the like. However, the compounds described in the literature are not suitable for synthesis,
In many cases, the same substituent is introduced into two N atoms. This is because when different substituents are introduced into the equivalent N atom, the existing method involves a multi-step production process (multi-step reaction), and there is a problem in the selectivity of the reaction. There were various problems such as being obtained as a mixture.

A conventionally known method for producing N-substituted-5-hydroxy-tetrahydro-2-pyrimidinone is described in International Publication No. WO94/19329.
A method is described in which an aliphatic diamine compound corresponding to the required structure is reacted with a suitable reducing agent in a suitable solvent, optionally a base. Not only are many diamines used in this method difficult to obtain, but they also require special reagents in the process of diamine production, and many industrial processes such as multiple steps are required. Is often difficult.

Further, N,N-unsubstituted 5-hydroxy-
As a method for synthesizing tetrahydro-2-pyrimidinone, there are Chemiste Berichte (Chem. Ber.), 3
4, p. 3289 (1901), electrolytic reduction of cyclic urea, U.S. Pat. No. 2,874,149, 1,3.
-A method using diamino-2-propanol and carbon monoxide as starting materials, 1,3 in U.S. Pat. No. 3,530,128.
-A method using diamino-2-propanol and a cyclic carbonate as raw materials, Journal of American Chemical Society (J. Am. Chem. Soc.),
72, p. 3205 (1950), a method of hydrolyzing 2-nitroamino-5-hydroxy-1,3-diaza-2-cyclohexene in water with a benzylamine catalyst, Journal of Organic Chemistry (J. Org. Chem.), Volume 61, 4175-41.
On page 79 (1996), a method using 1,3-diamino-2-propanol and S,S-dimethyldithiocarbonate as raw materials is known. Not only are these raw materials industrially difficult to obtain, but there are problems in introducing different substituents on the two N atoms as described above, and very expensive chemicals are required. It was an uneconomical method because it was used as a raw material and the yield was low.

Thus, an efficient method for producing N-substituted-5-hydroxy-tetrahydro-2-pyrimidinone has not been known so far. Further, by making N-substituted asymmetry, 5-position of 5-hydroxy-tetrahydro-2-pyrimidinone becomes an asymmetric carbon and it becomes optically active. However, the efficiency of such an optically active compound has hitherto been improved. There are no known examples of conventional manufacturing methods.

[0006]

DISCLOSURE OF THE INVENTION The present invention provides an efficient N-substituted-5-hydroxy-tetrahydro-2-pyrimidinone useful as a fiber treating agent, a resin raw material, a resin additive, an agricultural chemical intermediate and a pharmaceutical intermediate. Production method, by using an easily available optically active raw material, as various optically active uses, an optical resolving agent and its raw material or pesticide,
Optically active N-substituted asymmetric-5- that is a compound useful as various existing asymmetric sources such as pharmaceutical intermediates and other asymmetric catalysts
It is intended to provide an efficient method for producing hydroxy-tetrahydro-2-pyrimidinone.

[0007]

According to a first aspect of the present invention, the formula (1):

[0008]

[Chemical 6]

Tris-(2,3-epoxypropyl)-isocyanurate represented by the formula and the formula (2):

[0010]

[Chemical 7]

(In the formula (2), n is 0 or 1, and R is
¹ is an organic group having 1 to 36 carbon atoms which may contain one or more atoms selected from the group consisting of oxygen atom, nitrogen atom, sulfur atom and phosphorus atom, and R ² and R ³ are each a hydrogen atom, or It represents an organic group having 1 to 36 carbon atoms which may contain one or more atoms selected from the group consisting of oxygen atom, nitrogen atom, sulfur atom and phosphorus atom. ) Is used as a raw material, the formula (3):

[0012]

[Chemical 8]

(In the formula (3), * represents an asymmetric carbon, n is 0 or 1, and R ¹ is at least one atom selected from the group consisting of oxygen atom, nitrogen atom, sulfur atom and phosphorus atom. An organic group having 1 to 36 carbon atoms, which may contain R ^2, R ³
Each represents a hydrogen atom or an organic group having 1 to 36 carbon atoms which may contain one or more atoms selected from the group consisting of oxygen atom, nitrogen atom, sulfur atom and phosphorus atom. As a second aspect of the method for producing N-substituted-5-hydroxy-tetrahydro-2-pyrimidinone represented by the formula (1), the following (A) process and (B) process: (A) process: represented by formula (1) Formula (4) by reacting tris-(2,3-epoxypropyl)-isocyanurate with an amine of Formula (2):

[0014]

[Chemical 9]

(In the formula (4), * represents an asymmetric carbon, n is 0 or 1, and R ¹ is at least one atom selected from the group consisting of oxygen atom, nitrogen atom, sulfur atom and phosphorus atom. An organic group having 1 to 36 carbon atoms, which may contain R ^2, R ³
Each represents a hydrogen atom or an organic group having 1 to 36 carbon atoms which may contain one or more atoms selected from the group consisting of oxygen atom, nitrogen atom, sulfur atom and phosphorus atom. ), a step of obtaining an amine adduct of tris-(2,3-epoxypropyl)-isocyanurate, and (B) step: Tris-(2,3-obtained in step (A).
A step of decomposing an amine adduct of epoxypropyl)-isocyanurate, a method for producing N-substituted-5-hydroxy-tetrahydro-2-pyrimidinone represented by the formula (3), and (B) as a third aspect. In the step, the method for producing N-substituted-5-hydroxy-tetrahydro-2-pyrimidinone according to the second aspect, wherein the reaction is performed in the presence of at least one compound selected from the group consisting of a base or an onium salt as a catalyst, As four viewpoints, N in the equation (3) is
Formula (5) characterized in that it is produced from a -substituted-5-hydroxy-tetrahydro-2-pyrimidinone as a raw material:

[0016]

[Chemical 10]

(In formula (5), * represents an asymmetric carbon, n is 0 or 1, and R ¹ is at least one selected from the group consisting of oxygen atom, nitrogen atom, sulfur atom and phosphorus atom. An organic group having 1 to 36 carbon atoms which may contain an atom, R ² and R ³ each represent a hydrogen atom, or one or more atoms selected from the group consisting of an oxygen atom, a nitrogen atom, a sulfur atom and a phosphorus atom; It represents an organic group having 1 to 36 carbon atoms which may be included, A and B may be independently the same or different, and R ⁴ , R ⁵ and R ⁶ each represent a hydrogen atom, or an oxygen atom, N-substituted-5-hydroxy-tetrahydro-2-, which represents an organic group having 1 to 36 carbon atoms, which may contain one or more atoms selected from the group consisting of nitrogen atom, sulfur atom and phosphorus atom. As a fifth aspect of the method for producing a pyrimidinone derivative, the N-substituted-5-hydroxy-tetrahydro-2-pyrimidinone of the formula (3) obtained from any one of the first to third aspects is used. N− represented by the formula (5) described in the fourth aspect.
As a sixth aspect of the method for producing a substituted-5-hydroxy-tetrahydro-2-pyrimidinone derivative, tris-used as a raw material according to any one of the first to third aspects.
(2,3-epoxypropyl)-isocyanurate,
As a seventh aspect, a method for producing an optically active N-substituted-5-hydroxy-tetrahydro-2-pyrimidinone having the structure of formula (3) which is optically active tris-(2,3-epoxypropyl)-isocyanurate , Tris-(2,3-epoxypropyl) used as a raw material in the fifth aspect
-Isocyanurate is an optically active tris-(2,3-
Epoxypropyl)-isocyanurate of formula (5)
Optically active N-substituted-5-hydroxy- having the structure
As an eighth aspect of the method for producing a tetrahydro-2-pyrimidinone derivative, the amine used as a raw material in any one of the first to third aspects is an optically active amine,
And an optically active N-substituted-5-hydroxy-tetrahydro-2 having the structure of formula (3), which additionally comprises the step of separating the resulting diastereomers of N-substituted-5-hydroxy-tetrahydro-2-pyrimidinone. -The method for producing pyrimidinone, and as a ninth aspect, the amine used as a raw material in the fifth aspect is an optically active amine, and the diastereomer of the obtained N-substituted-5-hydroxy-tetrahydro-2-pyrimidinone derivative Having the structure of formula (5), which further comprises the step of separating
A method for producing a hydroxy-tetrahydro-2-pyrimidinone derivative.

[0018]

BEST MODE FOR CARRYING OUT THE INVENTION In the present invention, N-substituted-5-hydroxy-tetrahydro-2-pyrimidinone has a structure of formula (3).

Equations (2), (3) and (4) in the present invention
And R ¹ used in the formula (5) is an oxygen atom, a nitrogen atom,
The organic group having 1 to 36 carbon atoms which may contain one or more atoms selected from the group consisting of sulfur atom and phosphorus atom is shown. The organic group is not particularly limited, but is preferably an aliphatic hydrocarbon group such as an alkyl group, a cycloalkyl group, an alkylcycloalkyl group, an aromatic hydrocarbon group, a heterocycle, an alkylaromatic hydrocarbon group. , An alkoxy group, an alkoxyalkyl group, an alkylaminoalkyl group, an alkenyl group, an alkynyl group, an alkoxycarbonyl group and the like. R ¹ is an organic group having 1 to 36 carbon atoms, and preferably an organic group having 1 to 18 carbon atoms, which is composed of the above-exemplified atomic group.

R ² , R ³ , R ⁴ , R ⁵ and R ⁶ represent a hydrogen atom or may contain one or more atoms selected from the group consisting of oxygen atom, nitrogen atom, sulfur atom and phosphorus atom. An organic group having 1 to 36 carbon atoms is shown. The organic group is not particularly limited, but is preferably an aliphatic hydrocarbon group such as an alkyl group, a cycloalkyl group, an alkylcycloalkyl group, an aromatic hydrocarbon group, a heterocycle, an alkylaromatic hydrocarbon group. , An alkoxy group, an alkoxyalkyl group, an acyl group, an alkylsulfonyl group, a phenylsulfonyl group, an alkylaminoalkyl group, an alkenyl group, an alkynyl group, an alkoxycarbonyl group and the like. ^{R 2, R 3, R 4} , R 5 and R ⁶ is an organic group having a carbon number of 1 to 36 consisting of the exemplified atomic group is preferably an organic group having 1 to 18 carbon atoms.

More specifically, R ¹ , R ² , R ³ , R ⁴ ,
Examples of R ⁵ and R ⁶ are given below.

For example, the alkyl group may be a methyl group, an ethyl group, an n-propyl group, an isopropyl group, etc., and the cycloalkyl group may be a cyclopropyl group, a cyclobutyl group,
Examples thereof include a cyclopentyl group and a cyclohexyl group.

Examples of the alkylcycloalkyl group include a methylcyclobutyl group, an ethylcyclopentyl group and a hexylcyclohexyl group.

Examples of the aromatic hydrocarbon group include a phenyl group, a naphthyl group and a biphenyl group.

As the heterocycle, an organic group consisting of an oxygen-containing cyclic compound having a skeleton such as ethylene oxide, dioxane, furan and pyran; having a skeleton such as pyrrole, pyrrolidine, pyridine, imidazole, pyrimidine, triazine, indole, quinoline and purine. An organic group composed of a nitrogen-containing cyclic compound; an organic group composed of a sulfur-containing cyclic compound having a skeleton such as thiophene or thiopyran. Other examples include cyclic compounds containing arsenic or phosphorus atoms. Further, it may be a heterocycle containing two or more kinds of hetero atoms at the same time, and examples thereof include thiazole.

Examples of the alkyl aromatic hydrocarbon group include a benzyl group, a phenethyl group and a phenylpropyl group.

Examples of the alkoxy group include a methoxy group, an ethoxy group, a propoxy group, an n-butoxy group, a tert-butoxy group and a cyclohexyloxy group.

Examples of the alkoxyalkyl group include methoxymethyl group, methoxyethyl group, ethoxypropyl group and the like.

Examples of the acyl group include an acetyl group, a propionyl group, a butyryl group, a valeryl group and a benzoyl group.

Examples of the alkylsulfonyl group include a methylsulfonyl group, an ethylsulfonyl group and a butylsulfonyl group.

Examples of the aromatic sulfonyl group include benzenesulfonyl group, biphenylsulfonyl group, naphthylsulfonyl group and the like.

Examples of the alkylaminoalkyl group include monomethylaminomethyl group, dimethylaminomethyl group, ethylaminopropyl group, diethylaminopropyl group and diisopropylaminobutyl group.

Examples of the alkenyl group include vinyl group, 2-butenyl group, isobutenyl group, pentenyl group, hexenyl group and octenyl group.

Examples of the alkynyl group include ethynyl group, butynyl group and pentynyl group.

Examples of the alkoxycarbonyl group include a methoxycarbonyl group and a butoxycarbonyl group.

Of the above compounds, particularly preferred are aliphatic hydrocarbon groups such as alkyl groups, cycloalkyl groups and alkylcycloalkyl groups, aromatic hydrocarbon groups,
Heterocyclic organic groups, alkylaromatic hydrocarbon groups, alkoxy groups, alkoxyalkyl groups, alkenyl groups, alkynyl groups are mentioned. These are the stability of compounds and the stability and availability of raw materials used for production. Chosen from.

The organic group may be one or more selected from halogen group, hydroxyl group, alkoxy group, benzyloxy group, thiol group, amino group, cyano group, amidoxime group, nitro group, sulfonyl group and sulfoxyl group. It may have a substituent and may be the same or different. Particularly preferable among these substituents are a halogen group, a hydroxyl group, a cyano group, a nitroso group, and a nitro group. These substituents also have stability of a compound and stability and availability of raw materials used for production. Chosen for its ease of use.

Equations (2), (3) and (4) in the present invention
And R ¹ , R ² and R ³ represented by the formula (5) respectively represent the structures of the raw material, the intermediate and the product, and are common to all. For example, when benzylamine is used as the raw material, n used in formula (2) is 1, R ¹ represents a phenyl group, and R ² and R ³ represent hydrogen atoms. Furthermore, R ¹ and R ^{2 in the} compound represented by the formula (4) which is an intermediate, and R ¹ and R ^{2 in the} compound represented by the formula (3) and the formula (5)
And R ³ are all the same as in formula (2), n is 1, R ¹ represents a phenyl group, and R ² and R ³ represent hydrogen atoms.

A and B in the N-substituted-5-hydroxy-tetrahydro-2-pyrimidinone derivative represented by the formula (5) of the present invention may be the same or different.

The optically active N-substituted-5-hydroxy-tetrahydro-2-pyrimidinone derivative of the present invention has the following formula (6) as S-form,

[0041]

[Chemical 11]

The R-form has the following formula (7).

[0043]

[Chemical formula 12]

N represented by the preferred formula (3) of the present invention
A method for producing a -substituted-5-hydroxy-tetrahydro-2-pyrimidinone derivative and an optically active N-substituted-5-hydroxy-tetrahydro-2-pyrimidinone derivative is
As the step (A), tris-(2,3-) represented by the formula (1) is used.
The amine adduct of tris-(2,3-epoxypropyl)-isocyanurate represented by the formula (4), which is obtained by reacting epoxypropyl)-isocyanurate with the amine represented by the formula (2), After obtaining it, the step (B) is a method of decomposing this adduct.

The tris-(2,3-epoxypropyl)-isocyanurate represented by the formula (1) as a starting material in the production method of the present invention, which is produced by any known method, is preferably used in the present invention. it can. For example, a commercially available product, TEPIC, manufactured by Nissan Chemical Industries, Ltd.
As a product name, a high-purity product name TEPIC-S can be mentioned.

When optically active tris-(2,3-epoxypropyl)isocyanurate is used as a raw material, (2R,2'R,2"R) or (2S,2').
S,2″S) compound, and the production method thereof is not particularly limited. For example, it is not possible to dynamically divide a racemic form of tris(2,3-epoxypropyl)isocyanurate with an enzyme or the like. There is a simultaneous resolution method, and a preferable method is a method disclosed in JP-A No. 11-315078. This method involves reacting cyanuric acid with an optically active epichlorohydrin, followed by dehydration under reflux with water. This is a method in which a dehydrochlorination reaction occurs by dropping an aqueous solution of sodium oxide to obtain the objective optically active tris-(2,3-epoxypropyl)-isocyanurate.

The optically active or racemic tris-(2,3-epoxypropyl)-isocyanurate used in the present invention is preferably highly pure in view of the properties of its use.
Specifically, the purity is preferably 90% or more, more preferably 95% or more. Further, the optical purity when an optically active substance is used as a raw material influences the optical purity of the target product and is important, and preferably 80% e. e. As described above, more preferably 90% optical purity e. e. That is all.

The method of purification is not particularly limited, but for example, optically active tris-(2,3-epoxypropyl)-isocyanurate can be highly purified by recrystallization using a solvent such as methanol. It is possible to purify.

As the amine represented by the formula (2), which is one of the starting materials used in the production method of the present invention, R described above is used.
It is an amination product of the atomic group represented by ¹ , R ² and R ³ . For example, methylamine, butylamine, benzylamine,
3-cyanobenzylamine, 3-nitrobenzylamine, 3-benzyloxybenzylamine, phenethylamine, cyclohexylamine, cinnamylamine, allylamine, propargylamine, ethanolamine, propanolamine, methoxyethylamine, benzyloxyethylamine, dimethylaminoethylamine, Dimethylaminopropylamine, dibenzylaminoethylamine, chloroethylamine, fluoroethylamine, trifluoroethylamine, methoxyamine, allyloxyamine, benzyloxyamine, N,N-dimethylhydrazine, N,N-dibenzylhydrazine, glycine methyl ester, Alanine ethyl ester, valine methyl ester, β-alanine ethyl ester, glycinonitrile,
Examples thereof include phenylglycinonitrile, aniline, toluidine, chloroaniline, anthranilic acid ethyl ester, but the present invention is not limited thereto. Further, an optically active substance corresponding to these amines can be used.

In the present invention, a catalyst is used in the step (A) of reacting the tris-(2,3-epoxypropyl)-isocyanurate represented by the formula (1) with the amine represented by the formula (2). You can It can be used with any catalyst that accelerates the reaction of the epoxy compound with the amine, such as aluminum chloride as an acid catalyst,
Examples thereof include Lewis acids such as tin chloride, boron trifluoride, and ytterbium trifluoride, and lithium chloride, lithium bromide, and sodium bromide, which are salts of halogenated hydrocarbons with other alkali metals or alkaline earth metals. And so on. Further, titanium oxide, silica, or the like can be used as an inorganic oxide as an acid catalyst utilizing the acidity of the surface.

On the other hand, tris-(2 represented by the formula (4)
Examples of the catalyst used in the step (B) for decomposing the amine adduct of 3-epoxypropyl)-isocyanurate include:
It is preferable to add a basic substance or an onium salt.

Examples of the basic substance include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate, metal hydrides such as sodium hydride and potassium t-.
It is possible to use a metal alkoxide such as butoxide, an organometallic amide such as lithium diisopropylamide, an organometallic compound such as n-butyllithium, and an organic base such as pyridine, 4-dimethylaminopyridine, triethylamine, diethylisopropylamine, and dimethylbenzylamine. it can. In particular, it is preferable to use an inorganic base such as sodium hydroxide or potassium hydroxide, or an organic base such as dimethylbenzylamine.

The onium salt used in the present invention is
Examples thereof include ammonium salts, phosphonium salts, arsonium salts, stibonium salts, oxonium salts, sulfonium salts, selenonium salts, stannonium salts, and iodonium salts. Among them, quaternary ammonium salts or quaternary ammonium salts
The use of a primary phosphonium salt is preferable because side reactions can be suppressed, and a quaternary ammonium salt is particularly preferable because it can be reacted under mild conditions and a relatively good yield and purity can be obtained.

Next, the onium salts used in the method of the present invention will be specifically exemplified.

Preferred examples of the quaternary ammonium salt include triethylbenzylammonium halide, triethylbenzylammonium halide,
Examples include trioctylmethylammonium halide, tributylbenzylammonium halide, trimethylbenzylammonium halide and the like. One more
8-Diaza-8-benzylbicyclo[5.4.0]undecene-7,1,5-diaza-bicyclo[4.3.0]
Imidazole compounds such as nonene-5 or 1-methylimidazole, 1-benzylimidazole and pyridine,
Ammonium salts obtained by reacting an amine compound such as a substituted pyridine typified by picoline with a halogenated hydrocarbon such as benzyl halide, methyl halide, and ethyl halide may be exemplified as a suitable catalyst. it can.

Preferred examples of the quaternary phosphonium salt include tetran-butylphosphonium halides, tetraalkylphosphonium halides such as tetra-n-propylphosphonium halides, and triethylbenzylphosphonium halides. Halogenated trialkylbenzylphosphonium, halogenated triphenylmethylphosphonium, halogenated triphenylethylphosphonium and other halogenated triphenylmonoalkylphosphoniums, halogenated triphenylbenzylphosphonium, Examples thereof include halogenated tetraphenylphosphonium, halogenated tritolyl monoarylphosphonium, and halogenated tritolyl monoalkylphosphonium.

Examples of the halogen used as the counter ion of the onium salt in the production method of the present application include chlorine ion (C
l ^-), a bromine ion (Br ^-), iodide ion (I ^-) or the like can be exemplified as suitable. The quaternary ammonium salt becomes a quaternary ammonium base which shows strong basicity when the counter ion halogen ion is replaced with hydroxyl ion (OH ^- ) by the action of moist silver oxide or the action of sodium hydroxide. Is known,
These can also be used as preferred basic substances.

If necessary, a basic substance and an onium salt may be combined and reacted. For example, the reaction can be performed more efficiently by combining an onium salt such as trimethylbenzylammonium chloride or triphenylethylphosphonium bromide with a basic substance.

As a reaction mode, the reaction can be carried out only with tris-(2,3-epoxypropyl)-isocyanurate represented by the formula (1) and the amine represented by the formula (2), but under milder conditions. Tris-
It is preferable to dissolve (2,3-epoxypropyl)-isocyanurate and the amine of formula (2) in a solvent to carry out the reaction.

The solvent used in the step (A) for reacting tris-(2,3-epoxypropyl)-isocyanurate and the amine of the formula (2) in the process of the present invention is inert to the reaction. Well, for example, aromatic hydrocarbons such as toluene and chlorobenzene, ethers such as dioxane, dimethoxyethane and tetrahydrofuran, alcohols such as methanol, ethanol, isopropanol, 2-methoxyethanol and 2-ethoxyethanol,
Halogenated carbons such as dichloroethane and chloroform,
Ketones such as acetone and methyl ethyl ketone, nitriles such as acetonitrile, tertiary amines such as pyridine and triethylamine, amides such as N,N-dimethylformamide, sulfur compounds such as dimethyl sulfoxide, nitro compounds such as nitroethane and nitrobenzene. , Esters such as ethyl acetate, or a mixture thereof is used. When the solvent is used, the reaction temperature can be from minus 78° C. to the boiling point of the solvent. It is preferable to carry out the reaction between room temperature (20° C.) and the boiling point of the solvent.

Further, as the solvent used in the step (B) for decomposing the amine adduct of tris-(2,3-epoxypropyl)-isocyanurate represented by the formula (4) in the process of the present invention, for example, toluene, Aromatic hydrocarbons such as chlorobenzene, ethers such as dioxane, dimethoxyethane and tetrahydrofuran, alcohols such as 2-methoxyethanol and 2-ethoxyethanol, halogenated carbons such as dichloroethane and chloroform, ketones such as acetone and methyl ethyl ketone. , Nitriles such as acetonitrile, pyridine, third such as triethylamine
A secondary amine, an amide such as N,N-dimethylformamide, a sulfur compound such as dimethyl sulfoxide, a nitro compound such as nitroethane and nitrobenzene, an ester such as ethyl acetate, or a mixture thereof is used. Preferably, dimethylformamide, dimethylsulfoxide, 2-ethoxyethanol or dimethoxyethane, which is a solvent having a boiling point of 100° C. or higher, is used, and the reaction temperature is 100° C.
To the boiling point of the solvent is preferable.

Step (A) and (B) in the manufacturing method of the present application
Although the same solvent may be used as the solvent used when performing the step, tris-(2,3-epoxypropyl)-isocyanurate and the amine of the formula (2) are reacted in the step (A). After the reaction, the amine adduct of tris-(2,3-epoxypropyl)-isocyanurate represented by the formula (4) is isolated by a purification method such as recrystallization, liquid chromatography, distillation, and the like. Alternatively, the compound of formula (3) may be produced by a decomposition reaction in step (B) after changing to

The amount of the amine represented by the formula (2) used in the present invention is not particularly limited, but is preferably 3 mol to 100 mol per 1 mol of tris-(2,3-epoxypropyl)-isocyanurate. It is used in the range of 6 mol to 60 mol, more preferably 6 to 60 mol.

N-substituted-5-hydroxy-tetrahydro-2 represented by the formula (3) obtained by the method of the present invention
By using -pyrimidinone, the N-substituted-5-hydroxy-tetrahydro-2-pyrimidinone derivative represented by the formula (5) can be produced. This production method is not particularly limited, and it is possible to easily derive a disubstituted compound in which two different N-atoms in one molecule are introduced with different substituents by a known method.

[0065]

[Production of 1-benzyl-5-(S)-hydroxy-tetrahydro-2-pyrimidinone]

10 ml of dichloromethane was added to 1.04 g of (2S,2′S,2″S)-tris(2,3-epoxypropyl)isocyanurate, and 0.95 g of ytterbium triflate and 1.72 g of benzylamine were added at room temperature and reacted overnight. After the completion of the reaction, 3.7 g of a crude product of an adduct obtained by distilling off the solvent was dissolved in 20 ml of 2-ethoxyethanol, 0.4 g of sodium hydroxide was added, and the mixture was reacted under reflux. After the completion, 1N-hydrochloric acid was added to neutralize, ethyl acetate was added and the mixture was stirred, and the aqueous layer was concentrated and purified by reverse phase chromatography to obtain 1.0 g of the desired product.

Melting point: 124.5-125.5° C. ¹ H-NMR (ppm, CDCl ₃ ): 7.20-7.3
5ppm (m, 5H), 5.25ppm (bs, 1H), 4.
70ppm (d, 1H, J=15Hz), 4.36ppm
(D, 1H, J=15Hz), 4.07ppm (m, 1
H, J=13 Hz), 3.48 ppm (bs, 1H),
3.42ppm (d, 1H, J=13Hz), 3.30ppm
(Dd, 2H, J=13, 14Hz), 3.16ppm
(D, 1H, J=14 Hz) [α] _D +8.60° (c=1.0, EtOH) Optical purity: 95% e. e. (CHIRALPAK
AD, IPA/Hexane=2/8, flow ra
te 0.6 ml/min, 210 nm) Example 2 [1-benzyl-5-hydroxy-tetrahydro-2-
Production of pyrimidinone] 0.23 g of calcium chloride and tris(2,3-epoxypropyl)isocyanurate of 0.23 g.
2 ml of acetonitrile was added to 6 g, 0.81 g of benzylamine was added at room temperature, and the mixture was reacted overnight. After completion of the reaction, the solvent was distilled off, dichloromethane and water were added, and the mixture was stirred. 1.7 g of a crude product of an adduct obtained by distilling off the solvent of the dichloromethane layer, sodium hydroxide 0.08
g and 6 ml of N,N-dimethylformamide were added and reacted under reflux. After completion of the reaction, 1N-hydrochloric acid was added to neutralize, ethyl acetate was added and stirred, and the aqueous layer was concentrated and purified by reverse phase chromatography to obtain 0.58 g of the desired product.

Melting point: 126 to 128° C. ¹ H-NMR (ppm, CDCl ₃ ): 7.15 to 7.4
0 ppm (m, 5H), 5.11 ppm (bs, 1H), 4.
68ppm (d, 1H, J=15Hz), 4.42ppm
(D, 1H, J=15Hz), 4.08ppm (m, 1
H), 3.10 to 3.45 ppm (m, 4H), 1.85p
pm(bs,1H) This compound was acetylated with acetic anhydride and pyridine under ice cooling and then recrystallized to easily obtain a 5-acetyl compound.

Melting point: 188 to 189° C. ¹ H-NMR (ppm, CDCl ₃ ): 7.20 to 7.4
0 ppm (m, 5H), 5.60 ppm (bs, 1H), 5.
07ppm (m, 1H), 4.74ppm (d, 1H, J=1
5Hz), 4.36ppm (d, 1H, J=15Hz),
3.50 to 3.60 ppm (m, 1H), 3.35 to 3.
60ppm (m, 1H), 3.15-3.25ppm (m, 1H
H), 1.99 ppm (s, 3H) Example 3 [1-phenethyl-5-hydroxy-tetrahydro-2
-Production of pyrimidinone] 2.98 g of tris-(2,3-epoxypropyl)-isocyanurate was dissolved in 20 ml of acetonitrile, and calcium chloride 1.1 was added at room temperature.
4 g and (-)-phenethylamine 4.07 g were added and reacted overnight. After completion of the reaction, the solvent was distilled off, dichloromethane and water were added, and the mixture was stirred. The crude product of the adduct obtained by distilling off the solvent from the dichloromethane layer was dissolved in 20 ml of N,N-dimethylformamide, 0.41 g of sodium hydroxide was added, and the mixture was reacted under reflux. After completion of reaction, 1
After neutralizing by adding N-hydrochloric acid, ethyl acetate was added and stirred. The aqueous layer was concentrated to obtain 4.44 g of the desired product.

Melting point: 96 to 102° C. ¹ H-NMR (ppm, CDCl 3): 7.15 to 7.
40ppm (m, 5H), 5.90ppm (q, 1H, J=7
Hz), 4.80 ppm (bs, 1H), 3.98-4.
10 ppm (m, 1H), 3.33 to 3.48 ppm (m, 1
H), 3.18 to 3.31 ppm (m, 2H), 2.80
~ 3.10ppm (m, 1H), 2.20ppm (bs, 1H), 1.51ppm (d, 1H, J=7H
z) The 5-acetyl compound was easily obtained by acetylating this compound with acetic anhydride and pyridine under ice cooling.

Melting point: 133-138° C. ¹ H-NMR (ppm, CDCl ₃ ): 7.15-7.4
2ppm (m, 5H), 5.85 to 5.96ppm (m, 1
H), 5.30 to 5.41 ppm (m, 1H), 5.01p
pm (bs, 1H), 3.42 to 3.58 ppm (m, 1
H), 3.13 to 3.40 ppm (m, 2H), 2.92
~3.08ppm (m, 1H), 2.08~1.85ppm
(S+s, 3H), 1.50 to 1.46 ppm (d+d,
3H, J=7 Hz) This diastereomeric mixture could be separated by thin phase chromatography (AcOEt 100%).

Diastereomer A: melting point 125-126
°C, [α] _D -32.0° (c=0.56, EtOH) Diastereomer B: melting point 132-136°C, [α] _D
-63.9 (c=0.60, EtOH) Example 4 [1-isopropyl-5-hydroxy-tetrahydro-
Production of 2-pyrimidinone] To 1.0 g of calcium chloride and 1.2 g of tris(2,3-epoxypropyl)isocyanurate, 20 ml of acetonitrile was added, and at room temperature, 3.55 g of isopropylamine was added and reacted overnight. The calcium chloride was filtered off, the solvent was distilled off, and the crude product of the adduct was washed with acetonitrile to obtain 2.0 g of the adduct. 10 ml of ethylene glycol was added to 1.0 g of the adduct, and the mixture was reacted under reflux. After completion of the reaction, the solvent was distilled off and the residue was purified by reverse phase chromatography to obtain 0.6 g of the desired product.

¹ H-NMR (ppm, CDCl ₃ ): 6.
33ppm (bs, 1H), 4.60ppm (hep, 1H,
J=8 Hz), 4.26 ppm (bs, 1H), 4.10
~4.15ppm (m, 1H), 3.10~3.40ppm
(M, 4H), 1.10ppm (d, 3H, J=8H
z), 1.04 ppm (d, 3H, J=8 Hz) This compound was acetylated with acetic anhydride and pyridine under ice cooling and then recrystallized to easily obtain a 5-acetyl derivative.

¹ H-NMR (ppm, CDCl ₃ ): 6.2
2ppm (bs, 1H), 4.70ppm (hep, 1H, J
=7 Hz), 5.05 to 5.15 ppm (m, 1H),
3.15-3.60ppm (m, 4H), 2.08ppm
(S, 3H), 1.09ppm (d, 3H, J=7H
z), 1.04ppm (d, 3H, J=7Hz)

[0074]

INDUSTRIAL APPLICABILITY The present invention is useful as a fiber treating agent, a resin raw material, a resin additive, an agricultural chemical intermediate, or a pharmaceutical intermediate.
-Providing a process for preparing -substituted-5-hydroxy-tetrahydro-2-pyrimidinone. And for various optically active uses, an optically active N-substituted-5-hydroxy-tetrahydro-2-pyrimidinone useful as various existing chiral sources such as optical resolving agents and their raw materials, agricultural chemicals, pharmaceutical intermediates, and other asymmetric catalysts, and A method for producing the derivative is provided.

Front Page Continuation (72) Inventor Motohiko Hidaka 1 722, Tsuboi-cho, Funabashi City, Chiba Pref. Term, Central Research Laboratory, Nissan Chemical Industries, Ltd. 4H039 CA42 CA60 CG90

Claims (9)

[Claims] 1. Formula (1): Tris-(2,3-epoxypropyl)-isocyanurate represented by the formula: and a compound represented by the formula (2): (In the formula (2), n is 0 or 1, and R ¹ has 1 to 36 carbon atoms which may contain one or more atoms selected from the group consisting of oxygen atom, nitrogen atom, sulfur atom and phosphorus atom.
The organic groups R ² and R ³ each represent a hydrogen atom, or may have one or more atoms selected from the group consisting of oxygen atom, nitrogen atom, sulfur atom and phosphorus atom, and have 1 to 36 carbon atoms. Indicates a group. ) A compound represented by the formula (3): (In the formula (3), * represents an asymmetric carbon, n is 0 or 1, and R ¹ contains at least one atom selected from the group consisting of an oxygen atom, a nitrogen atom, a sulfur atom and a phosphorus atom. A good C1-C36 organic group, R ² and R ³ each represent a hydrogen atom, or may contain at least one atom selected from the group consisting of an oxygen atom, a nitrogen atom, a sulfur atom and a phosphorus atom. A method for producing N-substituted-5-hydroxy-tetrahydro-2-pyrimidinone represented by formula (1) to (36). 2. The following steps (A) and (B): (A) step: Tris-(2,3-epoxypropyl)-isocyanurate represented by the formula (1) and the formula (2). By reacting with an amine of formula (4): (In the formula (4), * represents an asymmetric carbon, n is 0 or 1, and R ¹ contains at least one atom selected from the group consisting of an oxygen atom, a nitrogen atom, a sulfur atom and a phosphorus atom. A good C1-C36 organic group, R ² and R ³ each represent a hydrogen atom, or may contain at least one atom selected from the group consisting of an oxygen atom, a nitrogen atom, a sulfur atom and a phosphorus atom. A step of obtaining an amine adduct of tris-(2,3-epoxypropyl)-isocyanurate represented by the formula (1 to 36), and (B) step: obtained in step (A). Tris-(2,3-
A method for producing an N-substituted-5-hydroxy-tetrahydro-2-pyrimidinone represented by the formula (3), which comprises a step of decomposing an amine adduct of epoxypropyl)-isocyanurate. 3. The N-substituted-5-hydroxy-tetrahydro- according to claim 2, wherein the reaction is carried out in the presence of at least one compound selected from the group consisting of a base and an onium salt as a catalyst in the step (B). Method for producing 2-pyrimidinone. 4. N-substituted-5-hydroxy-of formula (3)
Formula (5) characterized by being produced from tetrahydro-2-pyrimidinone as a raw material: (In the formula (5), * represents an asymmetric carbon, n is 0 or 1, and R ¹ contains at least one atom selected from the group consisting of oxygen atom, nitrogen atom, sulfur atom and phosphorus atom. However, the organic group having 1 to 36 carbon atoms, R ² and R ³ each represent a hydrogen atom, or may contain one or more atoms selected from the group consisting of oxygen atom, nitrogen atom, sulfur atom and phosphorus atom. Represents an organic group having 1 to 36 carbon atoms, and A and B may be the same or different, and R
⁴ , R ⁵ and R ⁶ each represent a hydrogen atom, or may have 1 to 3 carbon atoms which may contain one or more atoms selected from the group consisting of oxygen atom, nitrogen atom, sulfur atom and phosphorus atom.
6 represents an organic group. ) A method for producing an N-substituted-5-hydroxy-tetrahydro-2-pyrimidinone derivative represented by 5. N-substituted-5-hydroxy-of formula (3)
The N-substituted-5-hydroxy-tetrahydro represented by the formula (5) according to claim 4, wherein the tetrahydro-2-pyrimidinone used is the one obtained in any one of claims 1 to 3. -2-Method for producing pyrimidinone derivative. 6. The tris-(2,3-epoxypropyl)-isocyanurate used as a raw material in any one of claims 1 to 3 is an optically active tris-(2,
A process for producing an optically active N-substituted-5-hydroxy-tetrahydro-2-pyrimidinone having a structure of formula (3) which is 3-epoxypropyl)-isocyanurate. 7. Tris-used as a raw material in claim 5.
(2,3-epoxypropyl)-isocyanurate,
A method for producing an optically active N-substituted-5-hydroxy-tetrahydro-2-pyrimidinone derivative having a structure of formula (5) which is optically active tris-(2,3-epoxypropyl)-isocyanurate. 8. The amine used as a raw material in any one of claims 1 to 3 is an optically active amine,
And an optically active N-substituted-5-hydroxy-tetrahydro-2 having the structure of formula (3), which additionally comprises the step of separating the resulting diastereomers of N-substituted-5-hydroxy-tetrahydro-2-pyrimidinone. -Method for producing pyrimidinone. 9. The amine used as the raw material in claim 5, is an optically active amine, and the obtained N-substituted-5-
A method for producing an optically active N-substituted-5-hydroxy-tetrahydro-2-pyrimidinone derivative having the structure of formula (5), which additionally comprises the step of separating the diastereomers of the hydroxy-tetrahydro-2-pyrimidinone derivative.